EP4687988A2 - Composés thérapeutiques pour inhiber et réduire l'expression de protéines de surface cellulaire - Google Patents

Composés thérapeutiques pour inhiber et réduire l'expression de protéines de surface cellulaire

Info

Publication number
EP4687988A2
EP4687988A2 EP24720390.4A EP24720390A EP4687988A2 EP 4687988 A2 EP4687988 A2 EP 4687988A2 EP 24720390 A EP24720390 A EP 24720390A EP 4687988 A2 EP4687988 A2 EP 4687988A2
Authority
EP
European Patent Office
Prior art keywords
seq
nucleotides
protein
length
therapeutic compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24720390.4A
Other languages
German (de)
English (en)
Inventor
HoWon J. KIM
In-San Kim
Jay S. Kim
Sun-Hwa Kim
Ick-Chan Kwon
Jong Won Lee
Yoo Soo Yang
Hong Yeol Yoon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Institute of Science and Technology KIST
K2b Therapeutics Inc
Original Assignee
Korea Institute of Science and Technology KIST
K2b Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Institute of Science and Technology KIST, K2b Therapeutics Inc filed Critical Korea Institute of Science and Technology KIST
Publication of EP4687988A2 publication Critical patent/EP4687988A2/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C12N2310/141—MicroRNAs, miRNAs

Definitions

  • One embodiment of the invention provides a therapeutic compound comprising a conjugate configured to bind to a second protein expressed on a surface of a target cell, the conjugate comprising a first protein coupled to an API, wherein the conjugate is configured to bind to the second protein expressed on the surface of the target cell in a manner so as to inhibit an activity of the second protein, the conjugate is further configured to be internalized by the target cell upon binding to the second protein expressed on the surface of the target cell, the API is configured to be released from the conjugate after the conjugate has been internalized by the target cell, and the API is further configured to reduce the expression of the second protein expressed on the surface of the target cell after the API has been released from the conjugate, thereby further inhibiting the activity of the second protein, so that the conjugate and the API synergistically inhibit the activity of the second protein.
  • the second protein is PD-1 (SEQ ID NO: 18) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 1, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is a microRNA, the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to SEQ ID NO: 39. In some embodiments, the microRNA consists of SEQ ID NO: 39. In still other embodiments, the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 1. In some embodiments, the first protein is selected from the group consisting of an anti-PD-1 antibody and an antigenbinding fragment thereof.
  • the second protein is CD38 (SEQ ID NO: 19) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 2, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is a microRNA, the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:42-44.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO:42-44.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:2.
  • the first protein is selected from the group consisting of an anti-CD38 antibody and an antigen-binding fragment thereof.
  • the first protein is a CD38 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to SEQ ID NO:45.
  • the CD38 binding peptide may consist of SEQ ID NO:45.
  • the second protein is HER2 (SEQ ID NO:20) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 3, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3 ' overhang region of 0-5 nucleotides in length.
  • the API may be a microRNA, the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:73-78.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO:73-78.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:3.
  • the first protein is selected from the group consisting of an anti-HER2 antibody and an antigen-binding fragment thereof.
  • the first protein is a HER2 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to a peptide sequence selected from the group consisting of SEQ ID NO:46-59.
  • the HER2 binding peptide may consist of an amino acid sequence selected from the group consisting of SEQ ID NO:46-59.
  • the second protein is PD-L1 isoform A (SEQ ID NO:21) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 4, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is PD-L1 isoform C (SEQ ID NO:22) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 5, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:5.
  • the first protein is selected from the group consisting of an anti- PD-L1 isoform C antibody and an antigen-binding fragment thereof.
  • the second protein is IL4R isoform A (SEQ ID NO:23) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 6, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' over
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:6.
  • the first protein is selected from the group consisting of an anti- IL4R isoform A antibody and an antigen-binding fragment thereof.
  • the second protein is IL4R isoform C (SEQ ID NO:24) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 7, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:7.
  • the first protein is selected from the group consisting of an anti-IL4R isoform C antibody and an antigen-binding fragment thereof.
  • the API may be a microRNA, the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:94 and 98.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO:94 and 98.
  • the first protein is a IL4R binding peptide consisting of an amino acid at least 90% identical to SEQ ID NO:66.
  • the IL4R binding peptide may consist of SEQ ID NO:66.
  • second protein is IL6R isoform 1 (SEQ ID NO:25) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 8, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NON.
  • the first protein is selected from the group consisting of an anti-IL6R isoform 2 antibody and an antigen-binding fragment thereof.
  • the second protein is IL6R isoform 3 (SEQ ID NO:27) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 10, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 10.
  • the first protein is selected from the group consisting of an anti- IL6R isoform 3 antibody and an antigen-binding fragment thereof.
  • the second protein is IL6R isoform 4 (SEQ ID NO:29) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 28, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:28.
  • the first protein is selected from the group consisting of an anti- IL6R isoform 4 antibody and an antigen-binding fragment thereof.
  • the second protein is TL6R isoform 5 (SEQ ID NO:31) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 30, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:30.
  • the first protein is selected from the group consisting of an anti- IL6R isoform 5 antibody and an antigen-binding fragment thereof.
  • the first protein may be a IL6R binding peptide consisting of an amino acid at least 90% identical to SEQ ID NO:67.
  • the IL6R binding peptide may consist of SEQ ID NO:67.
  • the second protein is TNFR1 (SEQ ID NO:32) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 11, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is a microRNA, the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:99-102.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO:99-102.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 11.
  • the first protein is selected from the group consisting of an anti- TNFR1 antibody and an antigen-binding fragment thereof.
  • the first protein is a TNFR1 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to SEQ ID NO:68.
  • the TNFR1 binding peptide may consist of SEQ ID NO:68.
  • the second protein is TNFR2 (SEQ ID NO:35) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 14, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 14.
  • the first protein is selected from the group consisting of an anti- TNFR2 antibody and an antigen-binding fragment thereof.
  • the first protein is a TNFR1 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to a peptide sequence selected from the group consisting of SEQ ID NO:69-72.
  • the TNFR2 binding peptide may consist of an amino acid sequence selected from the group consisting of SEQ ID NO:69-72.
  • One embodiment provides a method of reducing inflammation in a mammalian subject in need thereof, the method comprising administering a therapeutically effective amount of the therapeutic compound to the mammalian subject.
  • the mammalian subject may be human.
  • Another embodiment of the invention provides a therapeutic compound comprising a conjugate configured to bind to a sodium-dependent glucose cotransporter expressed on a surface of a target cell, the conjugate comprising a glucose coupled to an API, wherein the conjugate is configured to bind to the sodium-dependent glucose cotransporter so as to be transported across a membrane of the target cell and into the target cell, the API is configured to be released from the conjugate after the conjugate has been transported across the membrane of the target cell and into the target cell, and the API is further configured to reduce the expression of the sodium-dependent glucose cotransporter expressed on the surface of the target cell after the API has been released from the conjugate.
  • the API may be coupled to the glucose by a linker and the linker may be a cleavable linker.
  • the API is selected from the group consisting of a siRNA and an antisense oligonucleotide.
  • the sodium-dependent glucose cotransporter is SGLT1 isoform 1 (SEQ ID NO:36) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 15, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 15.
  • the sodium-dependent glucose cotransporter is SGLT1 isoform 2 (SEQ ID NO:37) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 16, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 16.
  • the sodium-dependent glucose cotransporter is SGLT2 (SEQ ID NO:38) and the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 17, (b) the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and (c) the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 17.
  • One embodiment provides a method of treating diabetes in a mammalian subject in need thereof, the method comprising administering a therapeutically effective amount of the therapeutic compound to the mammalian subject.
  • the mammalian subject may be human.
  • a pharmaceutical composition comprising the therapeutic compound and a pharmaceutically acceptable carrier.
  • Fig. 1 shows an SDS-PAGE gel and an agarose gel demonstrating the production of a PD-L1 binding peptide-siRNA conjugate of the correct size, in accordance with embodiments of the invention.
  • FIG. 2 shows microscopy images showing the binding of a Cy5.54abeled PD-L1 binding peptide-siRNA conjugate to PD-L1 on the cell surface of CT26.CL25 cells, as demonstrated by significant Cy5.5 fluorescence on cells incubated with the Cy5.5-labeled PD-L1 binding peptide-siRNA conjugate (second from left), in accordance with embodiments of the invention.
  • FIG. 3 shows microscopy images showing that a Cy5.5-labeled PD-L1 binding peptide-siRNA conjugate is internalized by CT26.CL25 cells to a significantly greater degree than the unconjugated Cy5.5-labeled siRNA at 9 hours, 18 hours, and 24 hours after treatment with the Cy5.5-labeled PD-L1 binding peptide-siRNA or the unconjugated Cy5.5-labeled siRNA, in accordance with embodiments of the invention.
  • FIG. 4 shows microscopy images showing that a Cy5.5-labeled PD-L1 binding peptide-siRNA conjugate is internalized by Bl 6F 10 cells to a significantly greater degree than the unconjugated Cy5.5-labeled siRNA at 18 hours and 24 hours after treatment with the Cy5.5- labeled PD-L1 binding peptide-siRNA or the unconjugated Cy5.5-labeled siRNA, in accordance with embodiments of the invention.
  • Nuclei stained with Hoechst 33342 blue
  • Cy5.5 fluorescence red
  • Fig. 5 shows a bar chart of qRT-PCR results demonstrating a significant reduction in relative PD-L1 expression in Cy5.5-labeled PD-L1 binding peptide-siRNA conjugate-treated CT26.CL25 cells versus untreated CT26.CL25 cells, in accordance with embodiments of the invention.
  • Fig. 6 shows a bar chart demonstrating that pre-treatment of 4T1 cells with Cy5.5- labeled PD-L1 binding peptide-siRNA conjugate reduces the subsequent binding of an APC- labeled anti-PD-Ll antibody to a greater degree than pre-treatment of 4T1 cells with an unconjugated PD-L1 binding protein, in accordance with embodiments of the invention.
  • Fig. 7 shows a bar chart of Western blot results demonstrating a significant reduction in relative PD-L1 protein expression in Cy5.5-labeled PD-L1 binding peptide-siRNA conjugate-treated CT26.CL25 cells versus siRNA conjugate-only treated and untreated CT26.CL25 cells, in accordance with embodiments of the invention.
  • FIG. 8 shows microscopy images showing the binding of an EGFR binding peptide-siRNA conjugate to EGFR on the cell surface of A549 cells, as demonstrated by significant YOYO-1 staining on cells incubated with the YOYO- 1 -stained EGFR binding peptide-siRNA conjugate, in accordance with embodiments of the invention.
  • Untreated cells and cells treated with unconjugated YOYO- 1 -stained EGFR siRNA display no YOYO-1 staining.
  • Fig. 9 shows a bar chart of qRT-PCR results demonstrating a significant reduction in relative EGFR expression in EGFR binding peptide-siRNA conjugate-treated A549 cells versus untreated cells and cells treated with unconjugated EGFR siRNA, in accordance with embodiments of the invention.
  • Fig. 10 shows a bar chart of Western blot results demonstrating a significant reduction in relative EGFR expression in EGFR binding peptide-siRNA conjugate-treated A549 cells versus untreated cells and cells treated with unconjugated EGFR siRNA, in accordance with embodiments of the invention.
  • a “set” includes at least one member.
  • the therapeutic compounds described herein are conjugates comprising a “warhead” coupled to an active pharmaceutical ingredient (“API”).
  • the warhead may be a protein or a small molecule that binds to a particular protein expressed on the surface of a cell.
  • PD-1 binding peptide SEQ ID NO:40
  • SEQ ID NO:40 may be the warhead in a conjugate comprising PD-1 binding peptide (SEQ ID NO:40) coupled to an API.
  • PD-1 binding peptide (SEQ ID NO:40) binds PD-1 expressed on the surface of a cell.
  • glucose is the warhead in a conjugate comprising glucose coupled to an API.
  • Glucose binds to sodiumdependent glucose cotransporters expressed on the surface of a cell.
  • a “target cell” is a cell expressing a protein on its cell surface that a therapeutic compound binds, the expression of the protein on the cell surface of the target cell being reduced after said binding and subsequent internalization of the therapeutic compound by the target cell.
  • ‘ ‘Active pharmaceutical ingredient,” “API,” and the like means the non-warhead portion and the non-linker portion of a therapeutic compound that is biologically active, in accordance with embodiments of the invention.
  • Suitable active pharmaceutical ingredients (“APIs”) include nucleic acid molecules such as siRNA, miRNA, antisense oligonucleotides, and derivatives thereof, including, but not limited to, nucleic acid molecules comprising a modified nucleotide, backbone, sugar, and/or base.
  • “Complementarity,” as used herein regarding nucleic acid sequences, refers to the ability of a nucleic acid to forms hydrogen bonds with another nucleic acid sequence by Watson-Crick base pairing or wobble base pairing.
  • a percent complementarity indicates the percentage of nucleotides in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-Crick base pairing) with the nucleotides of a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementarity).
  • “Perfectly complementary,” and the like, means that all the contiguous nucleotides of a nucleic acid sequence will hydrogen bond with the same number of contiguous nucleotides in a second nucleic acid sequence (i.e., the nucleic acid sequence has 100% complementarity). “Complementary,” as used herein without further qualification, means that contiguous nucleotides of a nucleic acid sequence has a percent complementarity with contiguous nucleotides of a second nucleic acid sequence that is selected from the group consisting of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%.
  • a nucleic acid sequence that is 19 nucleotides in length and complementary to 14 nucleotides of a second nucleic acid sequence means that 14 contiguous nucleotides of the nucleic acid sequence has a percent complementarity with contiguous nucleotides of the second nucleic acid sequence that is selected from the group consisting of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100% complementarity.
  • a nucleic acid sequence that is 19 nucleotides in length and complementary to at least 15 contiguous nucleotides in a second nucleic acid sequence means that contiguous nucleotides of the nucleic acid sequence has a percent complementarity with at least 15 contiguous nucleotides of the second nucleic acid sequence that is selected from the group consisting of 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100% complementarity.
  • antibody refers to an immunoglobulin molecule that is typically composed of two identical pairs of polypeptide chains, each pair having one “heavy” (H) chain and one “light” (L) chain.
  • Human light chains are classified as kappa (K) and lambda (X).
  • Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region.
  • the heavy chain constant regions of IgD, IgG, and IgA are comprised of three domains, CHI, CH2 and CH3, and the heavy chain constant regions of IgM and IgE are comprised of four domains, CHI, CH2, CH3, and CH4.
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells).
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from the aminoterminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of each heavy/light chain pair (VH/VL) typically form an antibody’s antigen-binding site.
  • the term “antibody” is not limited by any particular method of producing the antibody. For example, it includes monoclonal antibodies, recombinant antibodies, and polyclonal antibodies.
  • human antibody refers to an antibody consisting of amino acid sequences of human immunoglobulin sequences only.
  • a human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell or in a hybridoma derived from a mouse cell.
  • Human antibodies may be prepared in a variety of ways known in the art.
  • humanized antibody refers to an antibody that contains some or all of the CDRs from a non-human animal antibody, while the framework and constant regions of the antibody contain amino acid residues derived from human antibody sequences. Humanized antibodies are typically produced by grafting CDRs from a mouse antibody into human framework sequences followed by back substitution of certain human framework residues for the corresponding mouse residues from the source antibody.
  • humanized antibody also refers to an antibody of non-human origin in which, typically in one or more variable regions, one or more epitopes have been removed that have a high propensity of constituting a human T- cell and/or B-cell epitope, for purposes of reducing immunogenicity.
  • the amino acid sequence of the epitope can be removed in full or in part. However, typically the amino acid sequence is altered by substituting one or more of the amino acids constituting the epitope for one or more other amino acids, thereby changing the amino acid sequence into a sequence that does not constitute a human T-cell and/or B-cell epitope.
  • the amino acids are substituted by amino acids that are present at the corresponding position(s) in a corresponding human variable heavy or variable light chain as the case may be.
  • an “antigen-binding fragment” of an antibody refers to a fragment of an antibody that binds to an antigen, comprising a constant and a variable domain of each of the heavy and the light chain of an antibody.
  • antigen-binding fragments include Fab fragments and F(ab’)2 fragments.
  • “Therapeutically effective amount” means an amount of a therapeutic compound or composition sufficient to provide a desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An appropriate “therapeutically effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • pharmaceutically acceptable carrier means solvents, carrier agents, diluting agents and the like which are usually used in the administration of pharmaceutical compounds.
  • the term “identical” as used in reference to two sequences means that the monomeric units of one of the sequences matches exactly the monomeric units of the other sequence when the two sequences are aligned. Two sequences that are exactly the same share 100% identity and are referred to as being 100% identical.
  • the monomeric unit of a protein/peptide sequence is an amino acid residue and the monomeric unit of a nucleic acid sequence is a nucleotide.
  • a sequence that is 90% identical to a second sequence means that 90% of the monomeric units of the sequence exactly match the monomeric units of the second sequence when the two sequences are aligned.
  • a protein having a first amino acid sequence that is 90% identical to second amino acid sequence of 20 amino acid residues means that, when the first sequence is aligned with the second sequence, the first sequence differs from the second sequence by two amino acid residues.
  • Sequence identity and sequence alignment are well-known to those of skill in the art.
  • cell surface proteins are known to play a role in the proliferation of cancers of various forms. These cell surface proteins include, e.g., programmed cell death protein 1 (“PD-1”), programmed cell death ligand 1 (“PD-L1”), cluster of differentiation 38 (“CD38”), and human epidermal growth factor receptor 2 (“HER2”). By binding and inhibiting one or more of these proteins on the surface of a cancer cell, cancer cell proliferation can be suppressed or eliminated.
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed cell death ligand 1
  • CD38 cluster of differentiation 38
  • HER2 human epidermal growth factor receptor 2
  • IL4R interleukin 4 receptor
  • IL6R interleukin 6 receptor
  • TNFR1 tumor necrosis factor receptor 1
  • TNFR2 tumor necrosis factor receptor 2
  • cell surface proteins such as sodium-dependent glucose cotransporter protein 1 (“SGLT-1”) and sodium-dependent glucose cotransporter protein 2 (“SGLT-2”), offer promising targets for treating diabetes.
  • SGLT-1 sodium-dependent glucose cotransporter protein 1
  • SGLT-2 sodium-dependent glucose cotransporter protein 2
  • novel therapeutic compounds useful for treating various conditions comprising a conjugate having a warhead (for example, a peptide configured to bind a cell surface protein on the surface of a cancer cell) coupled to an API that are configured to: (1) bind a cell surface protein expressed on the surface of a cell, thereby inhibiting the activity of the cell surface protein, and (2) be internalized by the cancer cell, thereby delivering the API into the cancer cell, the API being configured to be released from the conjugate after internalization by the cell and to reduce expression of the cell surface protein.
  • a warhead for example, a peptide configured to bind a cell surface protein on the surface of a cancer cell
  • an API that are configured to: (1) bind a cell surface protein expressed on the surface of a cell, thereby inhibiting the activity of the cell surface protein, and (2) be internalized by the cancer cell, thereby delivering the API into the cancer cell, the API being configured to be released from the conjugate after internalization by the cell and to reduce expression of the cell surface protein.
  • therapeutic compounds disclosed herein may be administered to a subject so as to produce a one- two punch effect, thereby inhibiting the activity of a cell surface protein selected from the group consisting of PD-1, PD-L1, CD38, FLER2, IL4R, IL6R, TNFR1, and TNFR2.
  • Table 1 provides “warhead” peptides that bind the indicated cell surface protein, in accordance with an embodiment of the invention. These warhead peptides may be coupled to an API so as to form a conjugate configured to deliver a one-two punch to a target cell. [0062] Table 1; Warhead Peptides and the Cell Surface Proteins they Bind
  • PD-1 Programmed cell death protein 1
  • T cells and B cells are types of immune checkpoint protein that regulates the activity of the immune system. It is expressed on the surface of immune cells, including T cells and B cells, and plays a crucial role in maintaining immune tolerance by inhibiting the activation and proliferation of immune cells.
  • PD-1 has also been found to be upregulated in cancer cells, leading to immune evasion and decreased immune response to the cancer cells. This allows the cancer cells to evade detection and attack by the immune system, leading to the growth and progression of the cancer.
  • monoclonal antibodies such as pembrolizumab and nivolumab
  • targeting PD-1 with monoclonal antibodies can enhance the immune response to cancer cells and improve outcomes in certain cancer types, including melanoma, non-small cell lung cancer, and renal cell carcinoma. Chen, L., & Mellman, I. (2014). Nature, 541 (7637), 321-330 and Balar, AV & Weber, JS. (2017) PD-1 and PD-L1 antibodies in cancer: current status and future directions, Cancer Immunol Immunother., 66(5): 551-564.
  • CD38 is a transmembrane protein that is expressed on the surface of various immune cells, including T cells, B cells, and myeloid cells, as well as on certain cancer cells. It is involved in various immune and signaling pathways, including the regulation of calcium levels, the activation of enzymes, and the modulation of immune responses.
  • HER2 is often overexpressed in certain types of cancer, including breast, ovarian, gastric, and pancreatic cancer. Overexpression of HER2 leads to an uncontrolled proliferation of cancer cells and can result in the development of aggressive and therapy-resistant tumors. The overexpression of HER2 in cancer cells has been identified as a key driver of tumor progression and is associated with a poor prognosis. In breast cancer, for example, HER2 overexpression is found in approximately 20% of cases and is associated with a more aggressive form of the disease and a higher risk of relapse.
  • Therapies targeting HER2 have been developed and have shown to be effective in the treatment of HER2-positive cancers.
  • These therapies include monoclonal antibodies such as trastuzumab and pertuzumab, which bind to HER2 and inhibit its signaling, and small molecule tyrosine kinase inhibitors such as lapatinib and neratinib, which block the activity of HER2.
  • Breast Cancer Chemosensitivity Advances in Experimental Medicine and Biology. Vol. 608. pp. 119-29 and Vranic, S. et al. (2021).
  • Programmed death-ligand 1(PD-L1) is a protein that is expressed on the surface of certain cells, including cancer cells. It belongs to the immune checkpoint family of proteins, which regulate the activity of the immune system. PD-L1 is able to bind to a receptor called PD- 1, which is expressed on the surface of immune cells called T cells. When PD-L1 and PD-1 bind together, they inhibit the activity of T cells, which can help to prevent the immune system from attacking normal cells. However, cancer cells can exploit this inhibitory pathway by expressing high levels of PD-L1, which helps them evade the immune system and continue to grow and spread.
  • Interleukin-4 receptor is a transmembrane protein that plays a key role in the immune system. It is expressed on various immune cells, including T-helper cells, B cells, and macrophages, and is activated by the cytokine interleukin-4 (IL-4).
  • IL-4 is a key cytokine involved in the immune response to infections and inflammation. It is primarily produced by T- helper 2(Th2) cells and promotes the differentiation of immune cells into Th2 cells, which are involved in the production of antibodies and the activation of eosinophils and mast cells.
  • a therapeutic compound of the invention comprises a first protein, the first protein being selected from the group consisting of (i) a PD-1 binding peptide consisting of an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NO:40 and SEQ ID NO:41 and (ii) an anti-PD-1 antibody or antigen binding fragment thereof, coupled to an API, the API being a microRNA consisting of a nucleic acid sequence at least 95% identical to SEQ ID NO: 39.
  • the PD-L1 binding peptide consists an amino acid sequence selected from the group consisting of SEQ ID NO:60-65.
  • the anti-PD- Ll isoform A antibody and antigen binding fragment thereof may be humanized.
  • the anti-PD- Ll isoform C antibody and antigen binding fragment thereof may be humanized.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 39, 79-96, and 97.
  • a method of treating cancer in a mammalian subject in need thereof is also provided, the method comprising administering to the subject a therapeutically effective amount of the therapeutic compound.
  • the cancer is selected from the group consisting of lung cancer, bladder cancer, and kidney cancer.
  • the IL4R binding peptide consists of SEQ ID NO:66.
  • the anti-IL4R isoform A antibody and antigen binding fragment thereof may be humanized.
  • the anti-IL4R isoform C antibody and antigen binding fragment thereof may be humanized.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 94 and SEQ ID NO: 98.
  • a therapeutic compound of the invention comprises a first protein, the first protein being selected from the group consisting of (i) a TNFR1 binding peptide consisting of an amino acid sequence that is at least 90% identical SEQ ID NO:68 and (ii) an anti-TNFRl antibody or antigen binding fragment thereof, coupled to an API, the API being a microRNA consisting of a nucleic acid sequence at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO: 99-102.
  • the TNFR1 binding peptide consists of SEQ ID NO:68.
  • the anti-TNFRl antibody and antigen binding fragment thereof may be humanized.
  • the microRNA consists of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 99-102.
  • a method of reducing inflammation in a mammalian subject in need thereof comprising administering to the subject a therapeutically effective amount of the therapeutic compound.
  • compositions containing at least one therapeutic compound as described herein either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants.
  • therapeutic compounds provided herein may be administered by any conventional route, in particular orally, parenterally, rectally, or by inhalation (e.g. in the form of aerosols).
  • compositions provided herein is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of a therapeutic compound provided herein and, typically, one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well-known to those skilled in the art of pharmacy, and nonlimiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • stabilizers include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, and the like.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a mammalian subject.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra- synovial and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol.
  • Example 1 Construction of PD-L1 Binding Peptide-siRNA Conjugate
  • a PD-L1 binding peptide-siRNA conjugate was prepared using azide and DBCO click chemistry.
  • An azide functionalized PD-L1 binding peptide (SEQ ID NO:60) ((Azidoacetic acid)-NYSKPTDRQYHF) and an anti-PD-Ll siRNA (having a dibenzocyclooctyne (DBCO) functionalized sense strand (SEQ ID NO: 12) (GACUCAAGAUGGAACCUGAdTdT-[DBCO]) and a Cy5.5-labeled antisense strand (SEQ ID NO: 13) (dTdTCUGAGUUCUACCUUGGACU- Cy5.5)) were mixed in a 2: 1 molar ratio, respectively.
  • DBCO dibenzocyclooctyne
  • Example 3 PD-L1 Binding Peptide-siRNA Conjugate is Internalized after Binding to PD-L1
  • CT26.CL25 cells were incubated, as described in Example 2, with either the PD- L1 binding peptide-siRNA conjugate of Example 1 or the unconjugated Cy5.5-labeled siRNA of Example 1. After 9 hours, 18 hours, and 24 hours of incubation, cells were then fixated with 4% paraformaldehyde (PF A) for 10 min and washed twice with DPBS.
  • PF A paraformaldehyde
  • B16F10 cells were also incubated with either the PD-L1 binding peptide-siRNA conjugate of Example 1 or the unconjugated Cy5.5-labeled siRNA of Example 1 and similarly fixated after 18 hours and 24 hours of incubation.
  • CT26.CL25 and Bl 6F 10 cells treated with the conjugate of Example 1 internalized the conjugate, the amount of internalization increasing with increased incubation time.
  • CT26.CL25 and B16F10 cells treated with unconjugated Cy5.5-labeled siRNA show significantly less Cy5.5 fluorescence, indicating a much lower amount of siRNA internalization.
  • CT26.CL25 cells were incubated, as described in Example 2, with the PD-L1 binding peptide-siRNA conjugate of Example 1. After 24 hours, RNA was extracted from the cells using a Qiagen RNeasy Plus kit according to the manufacturer’s protocol. RNA from untreated CT26.CL25 cells was also extracted.
  • RNA extraction was made using oligodT(20mer) (SEQ ID NO: 127) and Bioneer RT-PCR kit.
  • qRT-PCR was also performed on the extracted RNA using SYBR-green from Enzynomics. Six qRT-PCR reactions were run on each sample.
  • GAPDH expression was used as a control.
  • the following primers were used for both qRT-PCR and RT-PCR (shown in the gel of Fig. 5) of GAPDH and PD-L1 : a. GAPDH: CCACCCAGAAGACTGTGGAT (SEQ ID NO 33) and CACATTGGGGGTAGGAACAC (SEQ ID NO:34). b. PD-L1 : GCTCCAAAGGACTTGTACGTG (SEQ ID NO: 103) and TGATCTGAAGGGCAGCATTTC (SEQ ID NO: 104).
  • 1% TBE gel was used to visualize the RT-PCR bands.
  • the RT-PCR was as follows : initial denaturation 95°C 5min, denaturation 95°C 10 sec, annealing 60°C 15 sec, elongation 72°C 15 sec, final elongation 72°C 30 sec (20 cycles for GAPDH, 30 cycles for PD-L1).
  • qRT-PCR results shown in Fig. 5 demonstrate a significant reduction of PD-L1 expression in conjugate-treated cells versus untreated cells, indicating that the conjugate of Example 1 is capable of silencing PD-L1 RNA expression in CT26.CL25 cells after being internalized.
  • CT6.CL25 cells treated with the conjugate of Example 1 express less PD-L1 protein than untreated CT6.CL25 cells and CT6.CL25 cells treated with only the siRNA (siR) of the conjugate of Example 1.
  • Example 5 Treatment with PD-L1 Binding Peptide-siRNA Conjugate Reduces anti-PD-Ll Antibody Binding of 4T1 Cells more than Treatment with PD-L1 Binding Peptide Alone
  • the treatment with the PD-L1 binding peptide-siRNA conjugate reduces the subsequent binding of the APC-labeled antibody to a greater degree compared to both the untreated control and the PD-L1 binding protein treatment group.
  • the difference in percentage of APC-labeled antibody binding strongly suggests that, apart from blocking PD-L1 on the cell surface and/or causing a reduction of the amount of PD-L1 on the cell surface through receptor-mediated endocytosis, the conjugate also silences expression PD-L1 expression through RNA interference.
  • Example 7 EGFR Binding Peptide-siRNA Conjugate Binds Specifically to EGFR
  • Example 8 EGFR Binding Peptide-siRNA Conjugate Silences EGFR mRNA and EGFR Protein Expression
  • A549 cells were incubated, similar to that described in Example 2 for the PD-L1 binding peptide-siRNA conjugate, with the EGFR binding peptide-siRNA conjugate of Example 6. After 24 hours, RNA was extracted from the cells using a Qiagen RNeasy Plus kit according to the manufacturer’s protocol. RNA from untreated A549 cells was also extracted.
  • RNA extraction was made using oligodT(20mer) (SEQ ID NO: 127) and Bioneer RT-PCR kit.
  • Relative expression was determined by gel electrophoresis. For the gel analyzing the RT-PCR products, 1% TBE gel was used to visualize the RT-PCR bands.
  • the RT-PCR was as follows: initial denaturation 95°C 5min, denaturation 95°C 10 sec, annealing 60°C 15 sec, elongation 72°C 15 sec, final elongation 72°C 30 sec (20 cycles for GAPDH, 30 cycles for PD- Ll).
  • A549 cells treated with the conjugate of Example 6 express less EGFR protein than untreated A549 cells and A549 cells treated with only the siRNA (siR) of the conjugate of Example 6.
  • a therapeutic compound comprising: a conjugate configured to bind to a second protein expressed on a surface of a target cell, the conjugate comprising a first protein coupled to an API, wherein: the conjugate is configured to bind to the second protein expressed on the surface of the target cell in a manner so as to inhibit an activity of the second protein, the conjugate is further configured to be internalized by the target cell upon binding to the second protein expressed on the surface of the target cell, the API is configured to be released from the conjugate after the conjugate has been internalized by the target cell, and the API is further configured to reduce the expression of the second protein expressed on the surface of the target cell after the API has been released from the conjugate, thereby further inhibiting the activity of the second protein, so that the conjugate and the API synergistically inhibit the activity of the second protein.
  • the therapeutic compound of potential claim P2 wherein the linker is a cleavable linker.
  • P4 The therapeutic compound according to any one of the preceding potential claims, wherein the second protein consists of a sequence selected from the group consisting of SEQ ID NOs: 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 35, 36, 37, and 38.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 31, 32, 35, 36, 37, and 38.
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 1,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- 1 (SEQ ID NO: 18) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 1
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is PD-1 (SEQ ID NO: 18) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to SEQ ID NO: 39.
  • PIO The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is PD-1 (SEQ ID NO: 18) and wherein the API is a microRNA , the microRNA consisting of SEQ ID NO: 39.
  • Pl 1 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein consists of a second protein amino acid sequence at least 90% identical to PD- 1 (SEQ ID NO: 18) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to SEQ ID NO: 39.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- 1 (SEQ ID NO: 18) and wherein the API is a microRNA , the microRNA consisting of SEQ ID NO: 39.
  • Pl 3 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is PD-1 (SEQ ID NO: 18) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 1.
  • P14 The therapeutic compound according to any one of potential claims Pl-3 and P - 13, wherein the first protein is selected from the group consisting of an anti-PD-1 antibody and an antigen-binding fragment thereof.
  • the second protein is CD38 (SEQ ID NO: 19) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 2,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to CD38 (SEQ ID NO: 19) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 2
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is CD38 (SEQ ID NO: 19) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:42-44.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to CD38 (SEQ ID NO: 19) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO:42-44.
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 3,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is HER2 (SEQ ID NO:20) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:73-78.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to HER2 (SEQ ID NO:20) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:73-78.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to HER2 (SEQ ID NO:20) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO:73-78.
  • the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:3.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to HER2 (SEQ ID NO:20) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:3.
  • P36 The therapeutic compound according to any one of potential claims Pl-3 and P28- 35, wherein the first protein is selected from the group consisting of an anti-HER2 antibody and an antigen-binding fragment thereof.
  • the second protein is PD-L1 isoform A (SEQ ID NO:21) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 4,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform A (SEQ ID NO:21) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 4,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is PD-L1 isoform C (SEQ ID NO:22) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 5,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- LI isoform C (SEQ ID NO:22) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 5,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:39, 79-96, and 97.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform A (SEQ ID NO:21) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:39, 79-96, and 97.
  • P45 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is PD-L1 isoform A (SEQ ID NO:21) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 39, 79- 96, and 97.
  • the second protein is PD-L1 isoform A (SEQ ID NO:21)
  • the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 39, 79- 96, and 97.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform A (SEQ ID NO:21) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 39, 79-96, and 97 P47.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform C (SEQ ID NO:22) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO: 39, 79-96, and 97.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform C (SEQ ID NO:22) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 39, 79-96, and 97.
  • P51 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is PD-L1 isoform A (SEQ ID NO:21) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:4.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to PD- L1 isoform A (SEQ ID NO:21) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:4.
  • P53 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is PD-L1 isoform C (SEQ ID NO:22) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15—25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 5.
  • the first protein is a PD-L1 binding peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 60-65.
  • the second protein is IL4R isoform A (SEQ ID NO:23) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 6,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL4R isoform A (SEQ ID NO:23) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 6,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is IL4R isoform C (SEQ ID NO: 24) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 7,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL4R isoform C (SEQ ID NO:24) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 7,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL4R isoform C (SEQ ID NO:24) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 94 and 98.
  • the second protein is IL6R isoform 1 (SEQ ID NO:25) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 8,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 8,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is IL6R isoform 2 (SEQ ID NO:26) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 9,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 2 (SEQ ID NO:26) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 9,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is IL6R isoform 3 (SEQ ID NO:27) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 10,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 3 (SEQ ID NO:27) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 10,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is 1L6R isoform 4 (SEQ ID NO:29) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 28,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 4 (SEQ ID NO:29) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 28,
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein is IL6R isoform 5 (SEQ ID NO:31) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 30,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 5 (SEQ ID NO:31) and wherein the API is an siRNA, the siRNA being a doublestranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • P89. The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is IL6R isoform 1 (SEQ ID NO:25) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:8.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 1 (SEQ ID NO:25) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:8.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 2 (SEQ ID NO:26) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 9.
  • P93 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is TL6R isoform 3 (SEQ ID NO:27) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 10.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 3 (SEQ ID NO:27) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 10.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 4 (SEQ ID NO:29) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:28.
  • P97 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is IL6R isoform 5 (SEQ ID NO:31) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:30.
  • the second protein is IL6R isoform 5 (SEQ ID NO:31) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:30.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to IL6R isoform 5 (SEQ ID NO:31) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:30.
  • P99 The therapeutic compound according to any one of potential claims Pl-3, P79-80, and P89-90, wherein the first protein is selected from the group consisting of an anti-IL6R isoform 1 antibody and an antigen-binding fragment thereof.
  • P 100 The therapeutic compound according to any one of potential claims Pl-3, P81-82, and P91-92, wherein the first protein is selected from the group consisting of an anti-IL6R isoform 2 antibody and an antigen-binding fragment thereof.
  • the second protein is TNFR1 (SEQ ID NO:32) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 11
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to TNFR1 (SEQ ID NO:32) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 11,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to TNFR1 (SEQ ID NO:32) and wherein the API is a microRNA , the microRNA consisting of a nucleic acid sequence, the nucleic acid sequence being at least 95% identical to a microRNA sequence selected from the group consisting of SEQ ID NO:99-102.
  • the second protein is TNFR1 (SEQ ID NO:32) and wherein the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO:99-102.
  • the API is a microRNA consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO:99-102.
  • Pl 12 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is TNFR1 (SEQ ID NO:32) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 11.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to TNFR1 (SEQ ID NO:32) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 11.
  • Pl 15 The therapeutic compound according to any one of potential claims Pl-3 and P106-113, wherein the first protein is a TNFR1 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to SEQ ID NO: 68.
  • the second protein is TNFR2 (SEQ ID NO:35) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 14,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to TNFR2 (SEQ ID NO:35) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 14,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • Pl 19 The therapeutic compound according to any one of potential claims Pl-3, wherein the second protein is TNFR2 (SEQ ID NO:35) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 14.
  • the second protein consists of a second protein amino acid sequence at least 90% identical to TNFR2 (SEQ ID NO:35) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 14.
  • P122 The therapeutic compound according to any one of potential claims Pl-3 and Pl 17-120, wherein the first protein is a TNFR2 binding peptide consisting of an amino acid sequence, the amino acid sequence being at least 90% identical to a peptide sequence selected from the group consisting of SEQ ID NO:69-72.
  • P123 The therapeutic compound according to any one of potential claims Pl-3 and Pl 17-120, wherein the first protein is a TNFR2 binding peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:69-72.
  • a therapeutic compound comprising: a conjugate configured to bind to a sodium-dependent glucose cotransporter expressed on a surface of a target cell, the conjugate comprising a glucose coupled to an API, wherein: the conjugate is configured to bind to the sodium-dependent glucose cotransporter so as to be transported across a membrane of the target cell and into the target cell, the API is configured to be released from the conjugate after the conjugate has been transported across the membrane of the target cell and into the target cell, and the API is further configured to reduce the expression of the sodium-dependent glucose cotransporter expressed on the surface of the target cell after the API has been released from the conjugate.
  • P125 The therapeutic compound of potential claim P124, wherein the API is coupled to the glucose by a linker.
  • the sodium-dependent glucose cotransporter is SGLT1 isoform 1 (SEQ ID NO:36) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 15,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT1 isoform 1 (SEQ ID NO:36) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 15,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • P130. The therapeutic compound according to any one of potential claims P124-126, wherein the sodium-dependent glucose cotransporter is SGLT1 isoform 1 (SEQ ID NO:36) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 15.
  • the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT1 isoform 1 (SEQ ID NO:36) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 15.
  • the sodium-dependent glucose cotransporter is SGLT1 isoform 2 (SEQ ID NO:37) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 16,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT1 isoform 2 (SEQ ID NO:37) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense
  • RNA strand wherein: (a) the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 16,
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • P134 The therapeutic compound according to any one of potential claims P124-126, wherein the sodium-dependent glucose cotransporter is SGLT1 isoform 2 (SEQ ID NO:37) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:16.
  • the sodium-dependent glucose cotransporter is SGLT1 isoform 2 (SEQ ID NO:37) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO:16.
  • the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT1 isoform 2 (SEQ ID NO:37) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 16.
  • the sodium-dependent glucose cotransporter is SGLT2 (SEQ ID NO:38) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the sense RNA strand is 19-29 nucleotides in length and is complementary to 14-29 nucleotides from the antisense RNA strand, and
  • the double stranded RNA molecule has a double stranded region of 14-29 nucleotides in length and a 3' overhang region of 0-5 nucleotides in length.
  • P 137. The therapeutic compound according to any one of potential claims P124-126, wherein the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT2 (SEQ ID NO:38) and wherein the API is an siRNA, the siRNA being a double-stranded RNA molecule including an antisense RNA strand and a sense RNA strand, wherein:
  • the antisense RNA strand is 19-29 nucleotides in length and is complementary to contiguous nucleotides of SEQ ID NO: 17,
  • the sodium-dependent glucose cotransporter consists of an amino acid sequence at least 90% identical to SGLT2 (SEQ ID NO:38) and wherein the API is an antisense oligonucleotide, the antisense oligonucleotide being 15-25 nucleotides in length and complementary to at least 15 contiguous nucleotides of SEQ ID NO: 17.
  • P141 A method of reducing inflammation in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the therapeutic compound according to any one of potential claims P59-123.
  • P142 A method of treating diabetes in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the therapeutic compound according to any one of potential claims P124-139.
  • a pharmaceutical composition comprising the therapeutic compound according to any one of potential claims Pl-139 and a pharmaceutically acceptable carrier.

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Abstract

L'invention concerne des composés thérapeutiques pour inhiber et réduire l'expression de protéines de surface cellulaire et des méthodes pour traiter le cancer, l'inflammation et le diabète à l'aide des composés thérapeutiques.
EP24720390.4A 2023-03-28 2024-03-27 Composés thérapeutiques pour inhiber et réduire l'expression de protéines de surface cellulaire Pending EP4687988A2 (fr)

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KR100872437B1 (ko) 2000-12-01 2008-12-05 막스-플랑크-게젤샤프트 츄어 푀르더룽 데어 비쎈샤프텐 에.파우. Ｒｎａ 간섭을 매개하는 작은 ｒｎａ 분자
US20050191653A1 (en) * 2003-11-03 2005-09-01 Freier Susan M. Modulation of SGLT2 expression
US7202218B2 (en) * 2005-08-03 2007-04-10 National Taiwan University Oligopeptide antagonist of interleukin-6
CA2621441C (fr) * 2005-09-12 2014-05-20 The Ohio State University Research Foundation Compositions et methodes pour le diagnostic et le traitement de cancers associes au gene bcl2
EP2199412A1 (fr) * 2008-12-10 2010-06-23 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Compositions et procédés pour le profilage de l'expression de micro-ARN de cellules souches cancéreuses
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CN106699889A (zh) * 2015-11-18 2017-05-24 礼进生物医药科技（上海）有限公司 抗pd-1抗体及其治疗用途
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US20200407717A1 (en) * 2018-02-14 2020-12-31 Ionis Pharmaceuticals, Inc. Methods of modulating antisense activity
CN108997478B (zh) * 2018-08-06 2021-09-21 中国药科大学 一种具有免疫检查点拮抗活性的多肽及其应用
WO2021076865A1 (fr) * 2019-10-18 2021-04-22 University Of Utah Research Foundation Conjugués d'administration de médicaments polymères et leurs procédés de fabrication et d'utilisation
US20230174616A1 (en) * 2020-04-29 2023-06-08 University Of Southern California Pd-l1 binding peptides
CA3174467A1 (fr) * 2020-05-13 2021-11-18 Chad PECOT Conjugues de ligand lie a un acide nucleique et leur utilisation pour l'administration a des cellules
US20240101695A1 (en) * 2020-09-01 2024-03-28 The Regents Of The University Of California Immunoglobulin e antibody compositions and methods of use
CN114632161B (zh) * 2020-12-16 2024-02-06 中国人民解放军军事科学院军事医学研究院 肿瘤坏死因子-α作为一种核酸基因药物体内递送载体的应用

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CN121620398A (zh) 2026-03-06
JP2026513237A (ja) 2026-04-23
AU2024248253A1 (en) 2025-10-09
KR20260003880A (ko) 2026-01-07
WO2024206405A2 (fr) 2024-10-03
IL323576A (en) 2025-11-01
WO2024206405A3 (fr) 2024-12-12
US20240325550A1 (en) 2024-10-03

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